Antidepressant medications are prescribed to millions of Americans, many of whom receive the drug for months to years. Despite increasingly sophisticated studies in animals and the development of more biochemically specific antidepressants, the therapeutic mechanism of action in man remains unknown. Comparison of effects on specific neurotransmitters and their metabolites in cerebrospinal fluid (CSF), plasma and urine in the same patients continues to expand and is complemented by physiologic, behavioral and neuroendocrine measures, allowing for clearer systems interpretations of changes. Findings of particular interest include the following: 1. We have now found that all chemically distinct antidepressant treatments which we have studied (seven to date) share the property of decreasing norepinephrine (NE) turnover; these include the "atypical" drugs bupropion and citalopram and, in initial studies, alprazolam. 2. Non-response after the atypical new putative antidepressant bupropion is associated with elevated plasma homovanillic acid, the major dopamine (DA) metabolite, and may be explained by the accumulation of high concentrations of pharmacologically active metabolites in plasma and CSF. 3. Monoamine oxidase inhibitors which decrease plasma NE as well as agents which increase it produce elevated urinary hydroxymelatonin, showing that despite decreased turnover antidepressants maintain or enhance NE function. 4. An apparently selective probe of serotonin (5HT) function and hence drug effects on that system has been developed by using intravenous administration of a 5HT uptake inhibitor at doses that do not cause nausea.